The lactam emerged as lead candidate due to
The lactam (6) emerged as lead candidate due to its high selectivity, outstanding potency (against ALK or in clinically known ALK mutants), low in vitro clearance, and low efflux potential. The lactam (6) was selected for further profiling against the resistant ALK mutants. Preclinical rat pharmacokinetic data (PK) for (6) demonstrated low plasma clearance, a moderate volume of distribution, a reasonable half-life, and a bioavailability of 100%. Furthermore, better preclinical PK and low protein binding provided high free plasma exposures and in rat in vivo data area under the curve (AUC) ratios of CSF to free plasma (0.31) and free hydroxylase to free plasma (0.21) suggested that compound (6) distributed into the CNS. A robust synthetic strategy efforts for lorlatinib from (7) through intramolecular Suzuki coupling or direct arylation published recently , . To develop amide-macrocycle featuring amino pyridine hinge-binding motif an optimized methodology provided (6) through careful protection of the aminopyridine (10) to effect the directed arylation  (Scheme 3). The use of cataCXium A as additive was critical to enable the reaction to occur in t-AmOH. To this end, amino-carbonylation of iodide (7) in the presence of (8) allowed the access to (9). Bromination using a slight excess of NBS delivered anticipated cyclization precursor (10) in regioselective manner. Direct cyclization (10) resulted in unproductive reaction pathway and yielded undesired des-halogenated product along with minor quantity of (6). Alternatively, the protected aminopyridine (11) as bis-acetamide derivative underwent Pd-catalyzed direct arylation in t-AmOH under diluted conditions (0.1 M) and yielded mixture of (6) and the corresponding mono- and bis-protected derivatives of (6). Further exhausted acid-mediated deprotection of crude mixture provided lorlatinib (6) as an amido-linked 12-membered unique macrocycle.
In conclusion, lorlatinib is an investigational medicine and its journey as ALK/ROS1 inhibitor has indicated that it is well tolerated and exhibits highly potent antitumor activity against known clinically acquired ALK mutations. Lorlatinib has shown promising efficacy, high selectivity and safety drug profile. The superior CNS penetrance has made lorlatinib a clinically promising candidate for treating ALK-driven lung cancers either as a single agent or in combination with other ALK inhibitors. Since the FDA approval of crizotinib as multi-targeted ALK/MET/ROS1 kinase inhibitor for ALK-rearranged NSCLC therapy, the researchers are focusing on ROS1-rearranged tumors, especially NSCLC. Lorlatinib is most potent and brain-penetrable inhibitor, presumably the most significant impact of lorlatinib would be in those patients where currently available TKIs have failed. The future few years may witness a speedy drive of clinical research in ROS1-rearranged tumors either using currently available ALK inhibitors or lorlatinib. Furthermore, combination therapies with lorlatinib may serve as ideal backbone to overcome and to prevent the resistant clones.
Conflicts of interest
Introduction Anaplastic lymphoma kinase (ALK) gene rearrangements are detected in approximately 5% of non-small cell lung cancers (NSCLCs) and lead to the expression of ALK fusion-proteins with strong oncogenic properties [, ]. The first approved ALK-inhibitor, crizotinib, demonstrated its superiority to standard chemotherapy in ALK-positive NSCLCs and remains for the time being the standard of care in this molecular subset of NSCLCs [, , , ]. However, a resistance mechanism inevitably occurs after a median of 10.9 months of treatment . Numerous effective next-generation ALK-inhibitors are in clinical development, and ceritinib and alectinib have received accelerated approval by the US Food and Drug Administration and the European Medicine Agency in crizotinib-refractory patients [, , , , ]. Alectinib is also more effective in first-line treatment compared to crizotinib as demonstrated by two phase III trials, and is now a new treatment option in this setting [, ]. These efficient and well tolerated inhibitors lead to a significant improvement of survival and quality of life in ALK-positive patients, supporting ALK testing for every newly diagnosed advanced NSCLC [, , , , , ].